Haploinsufficiency of the chromatin modifier gene KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome

The 17q21.31 microdeletion syndrome
is a clinically recognizable multisystem disorder that is
characterized by intellectual disability, hypotonia, epilepsy,
distinctive facial features, heart defects and urogenital
anomalies. The recurrent deletion encompasses five known protein
coding genes (CRHR1, SPPL2C, MAPT, STH, and KANSL1), but
the role of these genes in the pathogenesis of the syndrome was
unclear.

Researchers from the Human Genetics
Department at the Radboud University Nijmegen Medical Centre,
including 3 groups at the NCMLS, and collaborators in France,
UK and the US now report that haploinsufficiency of the chromatin
modifier gene KANSL1 is sufficient to cause the 17q21.31
microdeletion syndrome. This work was published online in Nature
Genetics, on April 29th.

In their interdisciplinary study,
the team of clinicians and researchers led by David Koolen and Bert
de Vries identified two small deletions and two heterozygous
mutations in KANSL1 that caused the typical phenotype.
They further supported the important role of the gene in neuronal
development and cognitive (dys)function by showing that genes
differentially expressed in patient-derived EBV-transformed cell
lines are enriched in genes with known neuronal/synaptic function,
and by demonstrating learning defects in a Drosophila
knockdown mutant of the KANSL1 orthologue
wah.